Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the central nervous system. It is characterized by demyelinating lesions in the white matter of the central nervous system that lead to neurological deficits (Sospedra M. and Martin R., Immunology of Multiple Sclerosis. Annu Rev Immunol., 23:683-747 (2005)). The pathogenesis of the disease is associated with the infiltration of immune cells, mainly activated T cells, into the brain (Sospedra M. and Martin R., Annu Rev Immunol., 23:683-747 (2005)). This infiltration is accompanied by a disruption of the blood-brain barrier (van Horssen J. et al., J Neuropathol Exp Neurol., 66:321-8 (2007)).
Intravenous immunoglobulins (IVIG) have been shown to be effective in the treatment of a number of autoimmune diseases including MS (Sospedra M. and Martin R., Immunology of Multiple Sclerosis. Annu Rev Immunol., 23:683-747 (2005)), but the exact mechanisms of action underlying the immunomodulatory activities of IVIG have not been fully explained. There are several models that try to explain the immunomodulatory efficacy of IVIG in patients suffering from autoimmune and inflammatory diseases (Kazatchkine M. D. et al., Mult Scler, 2:24-6; 33:24-26 (2000); Trebst C. and Stangel M., Curr. Pharm. Design, 12:241-2493 (2006)). These models include Fcγ-receptor-mediated immunomodulation (Sorensen P. S., Neurol Sci, 4:227-230 (2003)), modulation of idiotype/anti-idiotype networks (Samuelsson A. et al., Science, 291:484-6 (2001)), elimination of immunostimulating microbial products (Dalakas M. C., Ann Intern Med, 126:721-30 (1997)) and neutralizing antibodies against cytokines and chemokines (Bayry J. et al., Transfus Clin Biol., 10:165-9 (2003)). IVIG's potential to modify the balance between Th1 and Th2 cell immunoreactivity and to inhibit the formation of antibody/complement complexes have also been demonstrated (Andersson U. et al., Immunol Rev, 139:21-42 (1994); Bayry J. et al., Intravenous immunoglobulin in autoimmune disorders: An insight into the immunregulatory mechanisms).
The beneficial effects of IVIG in patients with MS were shown by a number of open clinical trials (Basta M. et al., Blood, 77:376-80 (1991)) and by four randomized double-blind clinical studies (Sorensen P. S. et al., Eur J Neurol, 9:557-563 (2002); Strasser-Fuchs S. et al., Mult Scler, 2:9-13 (2000); Sorensen P. S. et al., Neurology, 50:1273-1281 (1998); Lewanska M. et al., Eur J Neurol, 9:565-572 (2002)). IVIG decreased the relapse rate in MS patients and the number of gadolinium-enhancing lesions seen on brain magnetic resonance imaging (MRI) (Dudesek A. and Zettl U. K., J Neurol, 253; V/50-V/58)). Furthermore, IVIG was shown to suppress proliferation of activated peripheral T cells (Bayry J. et al., Neurol Sci, 4:217-221 (2003); Stangel M. and Gold R., Nervenarzt, (2005)). Auto-reactive peripheral T cells can cross the blood-brain barrier and are believed to be the main effector cells responsible for brain inflammation (Sospedra M. and Martin R., Annu Rev Immunol., 23:683-747 (2005); Helling N. et al., Immunol Res., 1:27-51 (2002)). Therefore, a modulation of T cell function by IVIG could explain the beneficial therapeutic effect of IVIG seen in MS patients.
Recently, we showed that IVIG is an effective alternative treatment for patients with acute exacerbations in relapsing-remitting multiple sclerosis (RRMS) (Elovaara I. et al., Intravenous Immunoglobulin is effective and well tolerated in the treatment of MS Relapse, manuscript submitted). Because peripheral auto-reactive T cells are believed to be responsible for brain inflammation in MS, we undertook to identify genes that are differentially regulated in peripheral T cells of patients with MS in acute exacerbation that are treated with IVIG. We reasoned that differences in gene expression profiles could provide important information about the potential mechanisms of action of IVIG treatment. Furthermore, changes in gene expression profiles could provide prognostic markers to predict treatment success. Such markers could also help to identify targets for developing new therapeutic agents.
Furthermore, increasing evidence has suggested a role for brain inflammation not only in MS but also in the pathogenesis of Alzheimers' disease and Parkinsons' disease (see, e.g., Wilms et al., Curr. Pharm. Des. 13:1925 (2007)). In particular microglia, the resident innate immune cells, play a major role in inflammatory processes of the brain and are known to be associated not only with MS but also with Alzheimers' disease and in Parkinsons' disease (see, e.g., Yamamoto et al., Am. J. Pathology 166:1475 (2006); Huang et al., FASEB 19:761 (2005); Kim et al., Exp. And Mol. Med. 38:333 (2006)). Thus, the present invention provides new prognostic markers to predict treatment success associated with the administration of intravenous immunoglobulin treatment as well as new therapeutic targets that may be exploited in the treatment of MS, e.g., relapsing-remitting multiple sclerosis (RRMS), Parkinsons' disease or Alzheimers disease.’